他克莫司与恩替卡韦联合治疗乙型肝炎病毒相关性肾小球肾炎的疗效和安全性：一项多中心、安慰剂对照、单盲随机临床试验。
The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial.
机构信息
The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Shantou University Medical College, Shantou, China.
出版信息
Ann Palliat Med. 2022 May;11(5):1762-1773. doi: 10.21037/apm-22-328.
BACKGROUND
The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN.
METHODS
Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events.
RESULTS
There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29).
CONCLUSIONS
In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier NCT03062813.
背景
乙型肝炎病毒相关性肾小球肾炎（HBV-GN）患者大量蛋白尿经抗病毒治疗后蛋白尿缓解率较低。他克莫司（TAC）在原发性肾病中有效，可通过抑制 HBV 与肝细胞钠牛磺胆酸共转运多肽结合来抑制 HBV 感染。本研究评估了 TAC 联合 ETV 与 ETV 单药治疗 HBV-GN 的疗效和安全性。
方法
在中国进行了这项前瞻性、随机、对照、多中心、单盲研究，招募了诊断为 HBV-GN 的患者。患者接受 TAC 和 ETV 治疗（TAC+ETV 组）或安慰剂和 ETV 治疗（ETV 组）26 周。疗效终点包括蛋白尿缓解，包括完全缓解（CR）和部分缓解（PR），24 小时蛋白尿（24 h UP）和 HBV DNA 滴度变化。安全性终点为 HBV 病毒学突破和不良事件的发生率。
结果
TAC+ETV 组有 14 例患者，ETV 组有 17 例患者。意向治疗分析显示，TAC+ETV 组有 64.3%（9/14）的患者和 ETV 组有 58.8%（10/17）的患者在 26 周时达到 PR 或 CR（P=0.38）。在第 14 周时，TAC+ETV 组有 42.9%（6/14）的患者和 ETV 组有 41.2%（7/17）的患者达到 PR 或 CR（P=0.23）。在第 26 周时，TAC+ETV 组的 24 h UP 从基线下降了 2.63±6.33 g，ETV 组下降了 1.42±4.34 g（P=0.55）。TAC+ETV 组的血清白蛋白从基线增加了 11.1±7.30 g/L，ETV 组增加了 3.81±5.09 g/L（P<0.001）。TAC+ETV 组的 HBV DNA 从基线下降了 1.49±2.04 log10，ETV 组下降了 2.47±2.08 log10（P=0.37）；ETV 组有 28.6%（4/14）的患者出现 HBV DNA 病毒学突破，而 TAC+ETV 组无此情况（P=0.29）。
结论
在成年 HBV-GN 患者中，与 ETV 单药治疗相比，TAC 和 ETV 联合治疗可显著提高血清白蛋白水平，而不会增加 HBV 再激活的风险。
试验注册
ClinicalTrials.gov 标识符 NCT03062813。
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